From a Ratchet Mechanism to Random Fluctuations Evolution of Hsp90's Mechanochemical Cycle

Ratzke, Christoph; Nguyen, Minh Nhat; Mayer, Mathias; Hugel, Thorsten

doi:10.1016/j.jmb.2012.07.026

Cited by 46 publications

(41 citation statements)

References 26 publications

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“…Expression and purification were done with the same protocol used for Hsp90 (ref. 23). With the exception that after the first HisTag purification the His-SUMO-p23 construct was dialysed against 50 mM sodiumphosphate, 200 mM NaCl, 20 mM imidazole, pH 7.8 buffer in presence of 1/100 mol Senp overnight at 4°C to cut off the HisTag-SUMO sequence.…”

Section: Molecular Biology and Protein Expression/purificationmentioning

confidence: 99%

“…Hsp90 is a dimer consisting of two elongated chains lying in parallel; each chain contains an amino-terminal (N-terminal) ATP binding site [14][15][16] . Large N-terminal openclose movements of the dimer occur in all investigated Hsp90 systems [17][18][19][20][21][22][23][24][25][26] . Likely, these open-close movements are stronger coupled to ATP hydrolysis in the bacterial Hsp90 (HtpG) compared with the eukaryotic yeast Hsp90, which might raise the question why Hsp90 lost some nucleotide control during evolution from prokaryotes to eukaryotes.…”

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confidence: 95%

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Four-colour FRET reveals directionality in the Hsp90 multicomponent machinery

2014

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In living organisms, most proteins work in complexes to form multicomponent protein machines. The function of such multicomponent machines is usually addressed by dividing them into a collection of two state systems at equilibrium. Many molecular machines, like Hsp90, work far from equilibrium by utilizing the energy of ATP hydrolysis. In these cases, important information is gained from the observation of the succession of more than two states in a row. We developed a four-colour single-molecule FRET system to observe the succession of states in the heat shock protein 90 (Hsp90) system, consisting of an Hsp90 dimer, the cochaperone p23 and nucleotides. We show that this multicomponent system is a directional ATP-dependent machinery. This reveals a previously undescribed mechanism on how cochaperones can modify Hsp90, namely by strengthening of the coupling between ATP hydrolysis and a kinetic step involved in the Hsp90 system resulting in a stronger directionality.

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Section: Molecular Biology and Protein Expression/purificationmentioning

confidence: 99%

mentioning

confidence: 95%

Four-colour FRET reveals directionality in the Hsp90 multicomponent machinery

2014

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“…[120,121] Whereas the ATPase cycle of the bacterial homologue HtpG is strongly coupled to nucleotide turnover and driven by a mechanical ratchet mechanism, the rate-limiting N-terminal conformational changes in yeast Hsp90 are nucleotide-independent and determined by slow thermal fluctuations between the open and closed states. [122] Nucleotide binding is not the only determinant for the Hsp90 conformation. Conformational changes in the Hsp90 chaperone cycle can be also modulated by cochaperones.…”

Section: Structural and Network-based Models Of Allosteric Interactiomentioning

confidence: 99%

Computational Studies of Allosteric Regulation in the Hsp90 Molecular Chaperone: From Functional Dynamics and Protein Structure Networks to Allosteric Communications and Targeted Anti‐Cancer Modulators

Verkhivker¹

2014

Israel Journal of Chemistry

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Computational studies of allosteric interactions have witnessed a recent renaissance fueled by growing interest in the modeling of complex molecular assemblies and biological networks. Allosteric interactions of the molecular chaperone Hsp90 with a diverse array of cochaperones and client proteins allow for molecular communication in signal transduction networks. In this review, recent developments in the understanding of allosteric interactions in the context of structural, functional, and computational studies of the Hsp90 chaperone are discussed. A comprehensive analysis of structural and network‐based models of protein allostery is provided. Computational and experimental approaches and advances in the understanding of Hsp90 interactions and regulatory mechanisms are reviewed to provide a systematic and critical view of the current progress and most challenging questions in the field. The current status and future prospects for translational research, bridging the basic science of chaperones with the discovery of anti‐cancer therapies, are also highlighted.

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“…Steady progress continues to be made on the structure-function relationships and reaction cycles of chaperones bound to individual client proteins [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16]. In this issue, however, we return to first principles, and shine the spotlight on the role of chaperones in biomolecular assemblies, as first defined for nucleosomes by Laskey [17].…”

Section: Chaperones At the Crossroads Of Life And Deathmentioning

confidence: 99%

Chaperones: needed for both the good times and the bad times

Quinlan

Ellis

2013

Phil. Trans. R. Soc. B

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In this issue, we explore the assembly roles of protein chaperones, mainly through the portal of their associated human diseases (e.g. cardiomyopathy, cataract, neurodegeneration, cancer and neuropathy). There is a diversity to chaperone function that goes beyond the current emphasis in the scientific literature on their undoubted roles in protein folding and refolding. The focus on chaperone-mediated protein folding needs to be broadened by the original Laskey discovery that a chaperone assists the assembly of an oligomeric structure, the nucleosome, and the subsequent suggestion by Ellis that other chaperones may function in assembly processes, as well as in folding. There have been a number of recent discoveries that extend this relatively neglected aspect of chaperone biology to include proteostasis, maintenance of the cellular redox potential, genome stability, transcriptional regulation and cytoskeletal dynamics. So central are these processes that we propose that chaperones stand at the crossroads of life and death because they mediate essential functions, not only during the bad times, but also in the good times. We suggest that chaperones facilitate the success of a species, and hence the evolution of individuals within populations, because of their contributions to so many key cellular processes, of which protein folding is only one.

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From a Ratchet Mechanism to Random Fluctuations Evolution of Hsp90's Mechanochemical Cycle

Cited by 46 publications

References 26 publications

Four-colour FRET reveals directionality in the Hsp90 multicomponent machinery

Four-colour FRET reveals directionality in the Hsp90 multicomponent machinery

Computational Studies of Allosteric Regulation in the Hsp90 Molecular Chaperone: From Functional Dynamics and Protein Structure Networks to Allosteric Communications and Targeted Anti‐Cancer Modulators

Chaperones: needed for both the good times and the bad times

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